NCT02487095|CompletedPhase 1/2ResultsFDA Drug

Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor, in Small Cell Cancers and Extrapulmonary Small Cell Cancers

A Phase I/II Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor in Small Cell Cancers

National Cancer Institute (NCI)ClinicalTrials.gov

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Other study identifiers

Sponsor study identifier

150150

Secondary identifiers

15-C-0150

Study Type

interventional

Actual enrollment (reported)

Locations

1 country

Sites

Timeline

Study Start

July 30, 2015

Actual (reported)

Primary Completion

February 24, 2021

Actual (reported)

Study Completion

December 26, 2024

Actual (reported)

Brief 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. 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.

Registry Overview

Registry-reported information. Elapsed time and enrollment totals alone do not measure study progress or recruitment pace.

Recruitment status: completed
Actual enrollment (reported): 62 participants
Study completion date: December 26, 2024
Actual (reported)
Listed locations: 1 countries · 1 sites

Trial Relationships

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Study Timeline

Dates and qualifiers reported by the registry. Estimated dates do not confirm that a milestone has occurred.

First Submitted
June 27, 2015
Actual (reported)
First Posted
July 1, 2015
Actual (reported)
Study Start
July 30, 2015
Actual (reported)
Primary Completion
February 24, 2021
Actual (reported)
Results Posted
April 12, 2022
Actual (reported)
Study Completion
December 26, 2024
Actual (reported)

Last Updated: April 13, 2025
Status Verified: March 2025
Results QC Date: March 17, 2022
Last Update Submitted: March 24, 2025

Conditions

Carcinoma, Non-Small -Cell Lung Ovarian Neoplasms Small Cell Lung Carcinoma Uterine Cervical Neoplasms Carcinoma, Neuroendocrine

Outcome Measures

Primary Outcomes (4)

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.
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.
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.
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.
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)
At disease progression - 0.68 months to 88.27 months, an Average Mean of 10.6 months
Phase II: Progression-free Survival (PFS)
At disease progression, an average of 3.28 months.
Phase I and Phase II: Duration of Response (DOR)
At disease progression, an average of 5.25 months.
Phase I: Overall Survival (OS)
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)
Day 1 Pre-Treatment, Post treatment on day 2, and Post treatment on day 3
+4 more secondary outcomes

Other Outcomes (1)

Phase I Number of Participants With a Dose Limiting Toxicity (DLT)
End of Cycle 1, approximately 3 weeks

Eligibility Criteria

Age18 Years+

Sexall

Healthy VolunteersNo

Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

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
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:
+6 more criteria

You may not qualify if:

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.

Contact the study team to confirm eligibility.

Related Publications (5)

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.

PMID: 25010037BACKGROUND

Josse 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.

PMID: 25269479BACKGROUND

Al-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.

PMID: 24934408BACKGROUND

Thomas 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.

PMID: 29252124RESULT

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.

PMID: 42820295DERIVED

Brief Summary

Registry Overview

Trial Relationships

Related Scientific Literature

Study Timeline

First Submitted

First Posted

Study Start

Primary Completion

Results Posted

Study Completion

Conditions

Keywords

Outcome Measures

Primary Outcomes (4)

Secondary Outcomes (9)

Other Outcomes (1)

Study Arms (2)

1/Phase I VX-970 (M6620) + topotecan

2/Phase II VX-970 (M6620) + topotecan

Interventions

Eligibility Criteria

You may qualify if:

You may not qualify if:

Sponsors & Collaborators

Study Sites (1)

Related Publications (5)

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MeSH Terms

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Interventions

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Intervention Hierarchy (Ancestors)

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