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

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.

Timeline

Start

2015-07-30

Primary completion

2021-02-24

Completion

2024-12-26

Publications

• Background 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.
• Background 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.
• Background 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.
• Results 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.

Drugs

Indications