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Protocol Details

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

This study is NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: No longer recruiting/follow-up only
Gender: Male & Female
Min Age: 18
Max Age: N/A

Referral Letter Required


Population Exclusion(s)

Pregnant Women;


RB1 Inactivation;
Kinase Inhibitor;
DNA Damage Response Network;
MYC And CCNE1 Activation;
Defective ATM-p53 Signaling Pathway

Recruitment Keyword(s)



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

Investigational Drug(s)

VX-970 (M6620)

Investigational Device(s)



Drug: Topotecan
Drug: VX-970 (M6620)

Supporting Site

National Cancer Institute


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.


To study the safety and efficacy of VX-970 (M6620) and topotecan in treating small cell lung cancer.


Adults at least 18 years old with small cell lung cancer.


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.

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-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:

--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 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 ALK translocations should have previously received appropriate 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


--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 CYP3A during the course of the study are ineligible. Lists including strong inhibitors and inducers of CYP 3A4 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.

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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.

Joss(SqrRoot)(Copyright) 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.

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.

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Principal Investigator

Referral Contact

For more information:

Anish Thomas, M.D.
National Cancer Institute (NCI)
NIHBC 10 - CRC BG RM 4-5330
(240) 760-7343

Linda C. Sciuto, R.N.
National Cancer Institute (NCI)
National Institutes of Health
Building 10
Room 8D44
10 Center Drive
Bethesda, Maryland 20892
(240) 760-6117

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office

Clinical Trials Number:


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