Carcinoma, Non-Small -Cell LungPhase 1/2NCT02487095
Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor, in Small Cell Cancers and Extrapulmonary Small Cell Cancers
A Phase 1/2 study testing Topotecan and VX-970 (M6620) in people with Carcinoma, Non-Small -Cell Lung and Ovarian Neoplasms, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
Background: Chemotherapy damages cancer cell deoxyribonucleic acid (DNA) so the cells die, and the tumor shrinks. But it may stop working in some people over time. This is partly due to efficient DNA damage repair mechanisms used by tumor cells. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Carcinoma, Non-Small -Cell Lung, Ovarian Neoplasms, Small Cell Lung Carcinoma
- What is being tested?
- Topotecan and VX-970 (M6620)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 62 participants
- Where
- 1 siteUnited States
- Study dates
- 30 Jul 2015to 26 Dec 2024
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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
- Both Phase I and Phase II:
- Male and female subjects greater than or equal to 18 years of age. Because no dosing adverse event data are currently available on the use of topotecan in combination with VX-970 (M6620) in subjects less than 18 years of age, children are excluded from this study, but will be eligible for future pediatrics trials.
- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
- Patients must have measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Subjects with evaluable, but not measurable disease will be eligible for Phase 1.
- Subjects must not have received chemotherapy or undergone major surgery within 4 weeks and radiotherapy within 24 hours prior to enrollment.
- Adequate organ functions
Show all 21Show fewer
- Hemoglobin greater than or equal to 9.0 g/dL
- Absolute neutrophil count greater than or equal to 1.5x10^9/L
- Platelets greater than or equal to 100x10^9/L
- Total Bilirubin less than or equal to 2.0 mg/dL
- Transaminases less than or equal to 2 x upper limit of normal (ULN) or if liver metastases were present, less than or equal to 3xULN
- Creatinine less than or equal to 1.5 mg/dL or creatinine clearance by Cockcroft-Gault formula greater than or equal to 60 mL/min
- Ability of subject to understand and the willingness to sign a written informed consent document.
- The effects of VX-970 (M6620) on the developing human fetus are unknown For this reason and because topotecan is known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during study participation and for 6 months after the last dose study therapy. 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.
- Phase I:
- Subjects with histologically confirmed small-cell lung cancer (SCLC), non- small cell lung cancer (NSCLC), ovarian cancer, cervical cancer, and neuroendocrine cancers will be eligible. Pathological confirmation of diagnosis will be done at National Cancer Institute (NCI) Laboratory of Pathology. Patients with other histologies will be allowed if no standard treatment options exist.
- At least one prior chemotherapy
- NSCLC subjects with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations should have previously received appropriate Food and Drug Administration (FDA) approved therapies in addition to prior chemotherapy
- Phase II:
- Histological confirmation of SCLC, or extrapulmonary small cell cancer. Although NCI confirmation of pathology is not required prior to starting treatment, every effort will be made to obtain outside pathology to be reviewed by an NCI pathologist.
- Subjects with both platinum-sensitive and platinum-refractory disease will be eligible
Who cannot join
- Subjects with tumor amenable to potentially curative therapy.
- Subjects who are receiving any other investigational agents.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to (study agent) or other agents used in study.
- Subjects with symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, subjects who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 1 week or on physiologic doses of steroids may be enrolled.
- Subjects requiring any medications or substances that are strong inhibitors or inducers of cytochrome p450, family 3, subfamily A (CYP3A) during the course of the study are ineligible. Lists including strong inhibitors and inducers of cytochrome p450 3A4 (CYP3A4) are provided.
- Subjects with evidence of severe or uncontrolled systemic disease, or any concurrent condition, which could compromise participation in the study, including, but not limited to, active or uncontrolled infection, immune deficiencies, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, stroke/cerebrovascular accident within the past 6 months, or psychiatric illness/social situations which would jeopardize compliance with the protocol.
- Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with VX-970 (M6620). In addition, these subjects are at increased risk of lethal infections when treated with marrow-suppressive therapy.
- Pregnant women are excluded from this study because topotecan is a Class D agent with the potential for teratogenic or abortifacient effects and because the effects of VX-970 (M6620) on the developing human fetus are currently unknown. In addition, because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with topotecan or VX-970 (M6620), breastfeeding should be discontinued if the mother is treated with these agents.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: A Phase I/II Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor in Small Cell Cancers
Background:
Chemotherapy damages cancer cell deoxyribonucleic acid (DNA) so the cells die, and the tumor shrinks. But it may stop working in some people over time. This is partly due to efficient DNA damage repair mechanisms used by tumor cells. VX-970 (M6620) may stop cancer cells from preventing the repair of DNA damaged by chemotherapy. The purpose of this study is to see if using the chemotherapy drug topotecan along with the drug VX-970 (M6620) will improve the response to chemotherapy.
Read more
Objective:
To study the safety and efficacy of VX-970 (M6620) and topotecan in treating small cell lung cancer.
Eligibility:
Adults at least 18 years old with small cell lung cancer.
Design:
Participants will be screened with medical history, physical exam, blood and heart tests, and scans. Most of these tests are part of their routine care. Most of these tests will be repeated throughout the study.
The study is set in 21-day cycles. Participants will get topotecan intravenous (IV) on days 1 through 5. They will get VX-970 (M6620) IV on day 5 alone or on day 5 and day 2.
Participants doctors will monitor them weekly for the first cycle, every 3 weeks after that.
For Part 1 of this Study the doses of topotecan and VX-970 (M6620) will be increased (according to the Protocol) to determine the maximum safe dose of the combination. The maximum safe dose of the combination is the dose at which no more than 1 in 6 people have an intolerable side effect.
More participants will join in Phase 2. They will take the drugs at the maximum safe dose, on the same schedule as the drugs were taken in Phase 1.
Participants will give samples of blood, hair, and tumor tissue (optional) at different times. They will discuss side effects at every visit.
A month after stopping taking the drugs, participants will have a physical exam and blood drawn. They will have follow-up phone calls every 3 months.
Read the detailed description
Background:
Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis.
Although highly responsive to chemotherapy initially, SCLC typically relapses quickly and becomes refractory to treatment within a few months.
There is only one Food and Drug Administration (FDA) approved treatment for patients with relapsed SCLC after first-line chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated single-strand deoxyribonucleic acid (DNA) breaks leading to lethal double-strand DNA breaks.
The survival of some SCLC cells despite initial tumor sensitivity to chemotherapy suggests the existence of a highly effective DNA damage response network.
SCLC is characterized by high replication stress (RB transcriptional corepressor 1 (RB1) inactivation, MYC and cyclin E1 (CCNE1) activation) and defective ataxia-telangiectasia mutated tumor protein p53 (ATM-p53) signaling pathway, which cause an excessive reliance on ataxia-telangiectasia rad 3-related (ATR) for survival following DNA damage.
We hypothesize that a combination of ATR kinase inhibition with DNA damaging agents such as topotecan will provide an attractive synthetically lethal therapeutic option for SCLC.
VX-970 is a potent and selective kinase inhibitor of ATR, and in vitro data support the hypothesis that ATR inhibition can improve SCLC responses to DNA damaging agents.
Primary objectives:
Phase 1: To identify the maximum tolerated dose (MTD) of topotecan in combination with VX-970.
Phase 2: To assess the efficacy with respect to clinical response rate of a combination of topotecan and VX-970 in the second-line treatment of patients with SCLC.
Eligibility:
Both Phase 1 and 2: Subjects must be greater than or equal to 18 years of age and have a performance status (Eastern Cooperative Oncology Group (ECOG) less than or equal to 2. Subjects must not have received chemotherapy or undergone major surgery within 4 weeks and radiotherapy within 24 hours prior to enrollment.
Phase 1: Subjects with histologically confirmed SCLC, non-small cell cancer (NSCLC), ovarian cancer, cervical cancer, and neuroendocrine cancers, and at least one prior chemotherapy. Patients with other histologies will be allowed if no standard treatment options exist. Patients with evaluable, but not measurable disease will be eligible for Phase I.
Phase 2: Subjects with histological confirmation of SCLC and one prior platinum-based chemotherapy. Patients with both platinum-sensitive and platinum-refractory disease will be eligible. Patients must have measurable disease to be eligible for Phase II.
Design:
Participants meeting inclusion and exclusion criteria will receive topotecan and VX-970 administered every 21 days (1 cycle), until disease progression or development of intolerable side effects.
Blood and hair samples will be collected at multiple time points during cycle 1 (pre-treatment on day 1, post treatment on days 2, and 3) for pharmacodynamic (PD) analyses.
Tumor biopsies, which are optional, will be obtained at baseline, during the first treatment cycle (approximately 15 hours after the first dose of VX-970 on day 3) and at disease progression except for subjects at the first dose level.
Participants at the first dose level will undergo biopsies on day 3 prior to third dose of topotecan.
Participants will be monitored weekly during the first cycle by clinic visit and basic labs.
Toxicity will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and tumor assessments will be made using computed tomography (CT) scans (chest, abdomen and pelvis) at baseline and after every 2 cycles according to Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1.
Follow-up for survival will be carried out every 3 months.
- Conditions
- Carcinoma, Non-Small -Cell Lung, Ovarian Neoplasms, Small Cell Lung Carcinoma, Uterine Cervical Neoplasms, Carcinoma, Neuroendocrine, Extrapulmonary Small Cell Cancer
- Being tested
- Topotecan, VX-970 (M6620)
- Keywords
- RB1 Inactivation, Kinase Inhibitor, DNA Damage Response Network, MYC And CCNE1 Activation, Defective ATM-p53 Signaling Pathway
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung, Ovarian Neoplasms, Small Cell Lung Carcinoma, Uterine Cervical Neoplasms, Carcinoma, Neuroendocrine
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TopotecanDrug
Also called Hycamtin
Topotecan (in combination with VX-970 (M6620) administered by intravenous (IV) Days 1-5 in a 21 day cycle, until disease progression or development of intolerable side effects.
VX-970 (M6620)Drug
Also called M6620
VX-970 (M6620 (in combination with Topotecan) administered by intravenous (IV) Day 5 or Days 2 and 5 in a 21 day cycle, until disease progression or development of intolerable side effects.
| Study group | Role | What they receive |
|---|---|---|
| 1/Phase I VX-970 (M6620) + topotecan | Experimental | VX-970 (M6620) + topotecan at escalating doses Receives: Drug: Topotecan; Drug: VX-970 (M6620) |
| 2/Phase II VX-970 (M6620) + topotecan | Experimental | VX-970 (M6620) + topotecan at maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) Receives: Drug: Topotecan; Drug: VX-970 (M6620) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Topotecan
MTD is defined as the dose level at which no more than 1 of 6 subjects experience a dose-limiting toxicity (DLT) during one cycle of treatment. A DLT is defined using the Common Terminology Criteria in Adverse Events (CTCAE) v4.0 and is related or possibly drug related, such as neutropenia Grade 4 for >7 days duration, febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection), or Grade 3 thrombocytopenia. Death due to drug related adverse events.
Measured: End of Cycle 1, approximately 3 weeks
Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of VX-970 (M6620)
MTD is defined as the dose level at which no more than 1 of 6 subjects experience a dose-limiting toxicity (DLT) during one cycle of treatment. A DLT is defined using the Common Terminology Criteria in Adverse Events (CTCAE) v4.0 and is related or possibly drug related, such as neutropenia Grade 4 for >7 days duration, febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection), or Grade 3 thrombocytopenia. Death due to drug related adverse events.
Measured: End of Cycle 1, approximately 3 weeks
Ph II: Number of Participants With a Clinical Response
Clinical response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.
Measured: Every two cycles (each cycle is 21 days) up to approximately 30 months.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Measured: Date treatment consent signed to date off study, approximately 9 months and 9 days for Ph I DL1, 42 months and 12 days for Ph I DL2, 15 months and 9 days for Ph I DL3, 17 months and 9 days for Ph I DL4, and 43 months and 22 days for Ph II DL4.
Secondary outcomes (9)
Phase I: Progression-free Survival (PFS)
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) and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Measured: At disease progression - 0.68 months to 88.27 months, an Average Mean of 10.6 months
Phase II: Progression-free Survival (PFS)
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) and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Measured: At disease progression, an average of 3.28 months.
Phase I and Phase II: Duration of Response (DOR)
DOR is measured from the time measurement criteria are met for Complete Response (CR) or Partial Response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented in response to the combination in both platinum sensitive and refractory patients. CR is disappearance of all non-target lesions and normalization of tumor marker level. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Measured: At disease progression, an average of 5.25 months.
Phase I: Overall Survival (OS)
OS is defined as the time from the on-study date until date of death or last follow-up.
Measured: On-study date until date of death, an average of 17.65 months.
Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment)
Hair samples were obtained from participants to determine a change in H2AX phosphorylation (named ƴH2AX) in the hair follicles when compared to baseline (day 1 pre-treatment). ƴH2AX signals were detected by immunochemistry (microscopy) by using an antibody specific against ƴH2AX that, in turn, was detected by a secondary antibody conjugated to a fluorescent probe. ƴH2AX signal intensity was measured in bottom of hair bulbs.
A change is defined as change in ƴH2AX signal (fluorescence intensity) in cells located toward the top of the hair bulbs.
Measured: Day 1 Pre-Treatment, Post treatment on day 2, and Post treatment on day 3
Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Peripheral Blood Mononuclear Cells (PBMCs) From Baseline (Day 1 Pre-Treatment)
PBMCs were obtained from participants to determine a change in H2AX phosphorylation (named ƴH2AX) in peripheral blood mononuclear cells (PBMCs) when compared to baseline (day 1 pre-treatment). ƴH2AX was detected by immunochemistry (microscopy) by using an antibody specific against ƴH2AX that, in turn, was detected by a secondary antibody conjugated to a fluorescent probe. Changes in ƴH2AX levels in PBMCs is defined as changes in numbers of ƴH2AX foci per cells.
Measured: Day 1 Pre-Treatment, Post treatment on day 2, and Post treatment on day 3
Percentage of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 14 (CD14)+ Monocytes Among Viable Cells, and Regulatory T Cells Among Cluster of Differentiation 4 (CD4)+ T Cells At Baseline and Post-Treatment
Blood samples were collected via venipuncture and immunophenotyping of PBMCs were performed by multiparameter flow cytometry for CD14+ monocytes among viable cells, and regulatory T cells among CD4+ T cells.
Measured: Baseline and 3 weeks post-treatment
Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment
Blood samples were collected via venipuncture and immunophenotyping of PBMCs were performed by multiparameter flow cytometry for CD8/CD4 T cell ratio.
Measured: Baseline and 3 weeks post-treatment
Phase II: Overall Survival (OS)
OS is defined as the time from the on-study date until date of death or last follow-up.
Measured: On-study date until date of death, an average of 12.22 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jul 2015 (estimated)
- Study start30 Jul 2015
- Primary completion24 Feb 2021
- Study completion26 Dec 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Carcinoma, Non-Small -Cell LungStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 62 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Anish Thomas, National Cancer Institute (NCI)
- Investigators
- Anish Thomas, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02487095
- Sponsor's protocol ID
- 150150
- Other IDs
- 15-C-0150
- Status last verified
- Mar 2025
- First submitted
- 27 Jun 2015
- Last updated
- 13 Apr 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Hall AB, Newsome D, Wang Y, Boucher DM, Eustace B, Gu Y, Hare B, Johnson MA, Milton S, Murphy CE, Takemoto D, Tolman C, Wood M, Charlton P, Charrier JD, Furey B, Golec J, Reaper PM, Pollard JR. Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970. Oncotarget. 2014 Jul 30;5(14):5674-85. doi: 10.18632/oncotarget.2158.
PubMed 25010037Josse R, Martin SE, Guha R, Ormanoglu P, Pfister TD, Reaper PM, Barnes CS, Jones J, Charlton P, Pollard JR, Morris J, Doroshow JH, Pommier Y. ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79. doi: 10.1158/0008-5472.CAN-13-3369. Epub 2014 Sep 30.
PubMed 25269479Al-Ahmadie H, Iyer G, Hohl M, Asthana S, Inagaki A, Schultz N, Hanrahan AJ, Scott SN, Brannon AR, McDermott GC, Pirun M, Ostrovnaya I, Kim P, Socci ND, Viale A, Schwartz GK, Reuter V, Bochner BH, Rosenberg JE, Bajorin DF, Berger MF, Petrini JH, Solit DB, Taylor BS. Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy. Cancer Discov. 2014 Sep;4(9):1014-21. doi: 10.1158/2159-8290.CD-14-0380. Epub 2014 Jun 16.
PubMed 24934408Thomas A, Redon CE, Sciuto L, Padiernos E, Ji J, Lee MJ, Yuno A, Lee S, Zhang Y, Tran L, Yutzy W, Rajan A, Guha U, Chen H, Hassan R, Alewine CC, Szabo E, Bates SE, Kinders RJ, Steinberg SM, Doroshow JH, Aladjem MI, Trepel JB, Pommier Y. Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors. J Clin Oncol. 2018 Jun 1;36(16):1594-1602. doi: 10.1200/JCO.2017.76.6915. Epub 2017 Dec 18.
PubMed 29252124Fialkoff 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
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor in Small Cell Cancers
- ClinicalTrials.gov ID
- NCT02487095
- Acronym / sponsor ID
- 150150
- Conditions
- Carcinoma, Non-Small -Cell Lung, Ovarian Neoplasms, Small Cell Lung Carcinoma, Uterine Cervical Neoplasms, Carcinoma, Neuroendocrine, Extrapulmonary Small Cell Cancer
- Keywords
- RB1 Inactivation, Kinase Inhibitor, DNA Damage Response Network, MYC And CCNE1 Activation, Defective ATM-p53 Signaling Pathway
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 62 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 30 Jul 2015 (actual)
- Primary completion
- 24 Feb 2021 (actual)
- Study completion
- 26 Dec 2024 (actual)
- First posted
- 1 Jul 2015 (estimated)
- Results
- Posted 12 Apr 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
Chemotherapy damages cancer cell deoxyribonucleic acid (DNA) so the cells die, and the tumor shrinks. But it may stop working in some people over time. This is partly due to efficient DNA damage repair mechanisms used by tumor cells. VX-970 (M6620) may stop cancer cells from preventing the repair of DNA damaged by chemotherapy. The purpose of this study is to see if using the chemotherapy drug topotecan along with the drug VX-970 (M6620) will improve the response to chemotherapy.
Objective:
To study the safety and efficacy of VX-970 (M6620) and topotecan in treating small cell lung cancer.
Eligibility:
Adults at least 18 years old with small cell lung cancer.
Design:
Participants will be screened with medical history, physical exam, blood and heart tests, and scans. Most of these tests are part of their routine care. Most of these tests will be repeated throughout the study.
The study is set in 21-day cycles. Participants will get topotecan intravenous (IV) on days 1 through 5. They will get VX-970 (M6620) IV on day 5 alone or on day 5 and day 2.
Participants doctors will monitor them weekly for the first cycle, every 3 weeks after that.
For Part 1 of this Study the doses of topotecan and VX-970 (M6620) will be increased (according to the Protocol) to determine the maximum safe dose of the combination. The maximum safe dose of the combination is the dose at which no more than 1 in 6 people have an intolerable side effect.
More participants will join in Phase 2. They will take the drugs at the maximum safe dose, on the same schedule as the drugs were taken in Phase 1.
Participants will give samples of blood, hair, and tumor tissue (optional) at different times. They will discuss side effects at every visit.
A month after stopping taking the drugs, participants will have a physical exam and blood drawn. They will have follow-up phone calls every 3 months.
Detailed description
Background:
Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis.
Although highly responsive to chemotherapy initially, SCLC typically relapses quickly and becomes refractory to treatment within a few months.
There is only one Food and Drug Administration (FDA) approved treatment for patients with relapsed SCLC after first-line chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated single-strand deoxyribonucleic acid (DNA) breaks leading to lethal double-strand DNA breaks.
The survival of some SCLC cells despite initial tumor sensitivity to chemotherapy suggests the existence of a highly effective DNA damage response network.
SCLC is characterized by high replication stress (RB transcriptional corepressor 1 (RB1) inactivation, MYC and cyclin E1 (CCNE1) activation) and defective ataxia-telangiectasia mutated tumor protein p53 (ATM-p53) signaling pathway, which cause an excessive reliance on ataxia-telangiectasia rad 3-related (ATR) for survival following DNA damage.
We hypothesize that a combination of ATR kinase inhibition with DNA damaging agents such as topotecan will provide an attractive synthetically lethal therapeutic option for SCLC.
VX-970 is a potent and selective kinase inhibitor of ATR, and in vitro data support the hypothesis that ATR inhibition can improve SCLC responses to DNA damaging agents.
Primary objectives:
Phase 1: To identify the maximum tolerated dose (MTD) of topotecan in combination with VX-970.
Phase 2: To assess the efficacy with respect to clinical response rate of a combination of topotecan and VX-970 in the second-line treatment of patients with SCLC.
Eligibility:
Both Phase 1 and 2: Subjects must be greater than or equal to 18 years of age and have a performance status (Eastern Cooperative Oncology Group (ECOG) less than or equal to 2. Subjects must not have received chemotherapy or undergone major surgery within 4 weeks and radiotherapy within 24 hours prior to enrollment.
Phase 1: Subjects with histologically confirmed SCLC, non-small cell cancer (NSCLC), ovarian cancer, cervical cancer, and neuroendocrine cancers, and at least one prior chemotherapy. Patients with other histologies will be allowed if no standard treatment options exist. Patients with evaluable, but not measurable disease will be eligible for Phase I.
Phase 2: Subjects with histological confirmation of SCLC and one prior platinum-based chemotherapy. Patients with both platinum-sensitive and platinum-refractory disease will be eligible. Patients must have measurable disease to be eligible for Phase II.
Design:
Participants meeting inclusion and exclusion criteria will receive topotecan and VX-970 administered every 21 days (1 cycle), until disease progression or development of intolerable side effects.
Blood and hair samples will be collected at multiple time points during cycle 1 (pre-treatment on day 1, post treatment on days 2, and 3) for pharmacodynamic (PD) analyses.
Tumor biopsies, which are optional, will be obtained at baseline, during the first treatment cycle (approximately 15 hours after the first dose of VX-970 on day 3) and at disease progression except for subjects at the first dose level.
Participants at the first dose level will undergo biopsies on day 3 prior to third dose of topotecan.
Participants will be monitored weekly during the first cycle by clinic visit and basic labs.
Toxicity will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and tumor assessments will be made using computed tomography (CT) scans (chest, abdomen and pelvis) at baseline and after every 2 cycles according to Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1.
Follow-up for survival will be carried out every 3 months.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1/Phase I VX-970 (M6620) + topotecan | Experimental | Drug: Topotecan, Drug: VX-970 (M6620)VX-970 (M6620) + topotecan at escalating doses |
| 2/Phase II VX-970 (M6620) + topotecan | Experimental | Drug: Topotecan, Drug: VX-970 (M6620)VX-970 (M6620) + topotecan at maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- Both Phase I and Phase II:
- Phase I:
- Phase II:
Key exclusion criteria (8 listed)
- Subjects with tumor amenable to potentially curative therapy.
- Subjects who are receiving any other investigational agents.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to (study agent) or other agents used in study.
- Subjects with symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, subjects who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 1 week or on physiologic doses of steroids may be enrolled.
- Subjects requiring any medications or substances that are strong inhibitors or inducers of cytochrome p450, family 3, subfamily A (CYP3A) during the course of the study are ineligible. Lists including strong inhibitors and inducers of cytochrome p450 3A4 (CYP3A4) are provided.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TopotecanAlso: HycamtinTopotecan (in combination with VX-970 (M6620) administered by intravenous (IV) Days 1-5 in a 21 day cycle, until disease progression or development of intolerable side effects. | Drug | 1/Phase I VX-970 (M6620) + topotecan, 2/Phase II VX-970 (M6620) + topotecan |
| VX-970 (M6620)Also: M6620VX-970 (M6620 (in combination with Topotecan) administered by intravenous (IV) Day 5 or Days 2 and 5 in a 21 day cycle, until disease progression or development of intolerable side effects. | Drug | 1/Phase I VX-970 (M6620) + topotecan, 2/Phase II VX-970 (M6620) + topotecan |
Primary outcome
Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Topotecan
Time frame: End of Cycle 1, approximately 3 weeks
MTD is defined as the dose level at which no more than 1 of 6 subjects experience a dose-limiting toxicity (DLT) during one cycle of treatment. A DLT is defined using the Common Terminology Criteria in Adverse Events (CTCAE) v4.0 and is related or possibly drug related, such as neutropenia Grade 4 for >7 days duration, febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection), or Grade 3 thrombocytopenia. Death due to drug related adverse events.
Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of VX-970 (M6620)
Time frame: End of Cycle 1, approximately 3 weeks
MTD is defined as the dose level at which no more than 1 of 6 subjects experience a dose-limiting toxicity (DLT) during one cycle of treatment. A DLT is defined using the Common Terminology Criteria in Adverse Events (CTCAE) v4.0 and is related or possibly drug related, such as neutropenia Grade 4 for >7 days duration, febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection), or Grade 3 thrombocytopenia. Death due to drug related adverse events.
Ph II: Number of Participants With a Clinical Response
Time frame: Every two cycles (each cycle is 21 days) up to approximately 30 months.
Clinical response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
Time frame: Date treatment consent signed to date off study, approximately 9 months and 9 days for Ph I DL1, 42 months and 12 days for Ph I DL2, 15 months and 9 days for Ph I DL3, 17 months and 9 days for Ph I DL4, and 43 months and 22 days for Ph II DL4.
Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
9 secondary outcomes
Phase I: Progression-free Survival (PFS)
Time frame: At disease progression - 0.68 months to 88.27 months, an Average Mean of 10.6 months
Phase II: Progression-free Survival (PFS)
Time frame: At disease progression, an average of 3.28 months.
Phase I and Phase II: Duration of Response (DOR)
Time frame: At disease progression, an average of 5.25 months.
Phase I: Overall Survival (OS)
Time frame: On-study date until date of death, an average of 17.65 months.
Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment)
Time frame: Day 1 Pre-Treatment, Post treatment on day 2, and Post treatment on day 3
Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Peripheral Blood Mononuclear Cells (PBMCs) From Baseline (Day 1 Pre-Treatment)
Time frame: Day 1 Pre-Treatment, Post treatment on day 2, and Post treatment on day 3
Percentage of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 14 (CD14)+ Monocytes Among Viable Cells, and Regulatory T Cells Among Cluster of Differentiation 4 (CD4)+ T Cells At Baseline and Post-Treatment
Time frame: Baseline and 3 weeks post-treatment
Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment
Time frame: Baseline and 3 weeks post-treatment
Phase II: Overall Survival (OS)
Time frame: On-study date until date of death, an average of 12.22 months.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Apr 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 25010037Hall AB, Newsome D, Wang Y, Boucher DM, Eustace B, Gu Y, Hare B, Johnson MA, Milton S, Murphy CE, Takemoto D, Tolman C, Wood M, Charlton P, Charrier JD, Furey B, Golec J, Reaper PM, Pollard JR. Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970. Oncotarget. 2014 Jul 30;5(14):5674-85. doi: 10.18632/oncotarget.2158.
- Background: PubMed 25269479Josse R, Martin SE, Guha R, Ormanoglu P, Pfister TD, Reaper PM, Barnes CS, Jones J, Charlton P, Pollard JR, Morris J, Doroshow JH, Pommier Y. ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79. doi: 10.1158/0008-5472.CAN-13-3369. Epub 2014 Sep 30.
- Background: PubMed 24934408Al-Ahmadie H, Iyer G, Hohl M, Asthana S, Inagaki A, Schultz N, Hanrahan AJ, Scott SN, Brannon AR, McDermott GC, Pirun M, Ostrovnaya I, Kim P, Socci ND, Viale A, Schwartz GK, Reuter V, Bochner BH, Rosenberg JE, Bajorin DF, Berger MF, Petrini JH, Solit DB, Taylor BS. Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy. Cancer Discov. 2014 Sep;4(9):1014-21. doi: 10.1158/2159-8290.CD-14-0380. Epub 2014 Jun 16.
- Results publication: PubMed 29252124Thomas A, Redon CE, Sciuto L, Padiernos E, Ji J, Lee MJ, Yuno A, Lee S, Zhang Y, Tran L, Yutzy W, Rajan A, Guha U, Chen H, Hassan R, Alewine CC, Szabo E, Bates SE, Kinders RJ, Steinberg SM, Doroshow JH, Aladjem MI, Trepel JB, Pommier Y. Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors. J Clin Oncol. 2018 Jun 1;36(16):1594-1602. doi: 10.1200/JCO.2017.76.6915. Epub 2017 Dec 18.
- Derived from this study: PubMed 42820295Fialkoff 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anish Thomas, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Topotecan and VX-970 (M6620) in people with Carcinoma, Non-Small -Cell Lung and Ovarian Neoplasms, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Apr 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Topotecan (time frame: End of Cycle 1, approximately 3 weeks). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02487095, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2025.