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

Study Purpose

Background: Chemotherapy damages cancer cell 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 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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion Criteria

  • -

    INCLUSION CRITERIA:

    - 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.
  • - ECOG performance status less than or equal to 2 - Patients must have measurable disease, per 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 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 SCLC, 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 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

    EXCLUSION CRITERIA:

    - 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.
  • - 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 Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT02487095
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1/Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

National Cancer Institute (NCI)
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Anish Thomas, M.D.
Principal Investigator Affiliation National Cancer Institute (NCI)
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

NIH
Overall Status Recruiting
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Carcinoma, Non-Small -Cell Lung, Ovarian Neoplasms, Small Cell Lung Carcinoma, Uterine Cervical Neoplasms, Carcinoma, Neuroendocrine, Extrapulmonary Small Cell Cancer
Study Website: View Trial Website
Additional Details

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 FDA approved treatment for patients with relapsed SCLC after first-line chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated single-strand DNA breaks leading to lethal doublestrand 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 (RB1 inactivation, MYC and CCNE1 activation) and defective ATM-p53 signaling pathway, which cause an excessive reliance on 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 (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, NSCLC, ovarian cancer, cervical cancer, and neuroendocrine cancers, and at least one prior chemotherapy. Patients with other histolgies 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 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 CTCAE version 4.0, and tumor assessments will be made using 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.

Arms & Interventions

Arms

Experimental: 1/Phase I

VX-970 + (M6620) topotecan at escalating doses

Experimental: 2/Phase II

VX-970 (M6620) + topotecan at MTD/RP2D

Interventions

Drug: - Topotecan

Topotecan (incombination with M6620) administered by IV Days 1-5 in a 21 day cycle, until disease progression or development of intolerable side effects.

Drug: - VX-970 (M6620)

M6620 (in combination with Topotecan) administered by IV Day 5 or Days 2 and 5 in a 21 day cycle, until disease progression or development of intolerable side effects.

Contact a Trial Team

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Bethesda, Maryland

Status

Recruiting

Address

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892

Site Contact

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

lsciuto@mail.nih.gov

888-624-1937

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